Interferon Responsiveness and Anifrolumab Binding Determined by B Cell Phenotype 2784

Abstract Description Background Interferon (IFN) plays a critical role in systemic lupus erythematous (SLE). CD11c+ T-Bet+ autoimmune-associated B cells (ABC) are a therapeutic target of interest expanded in SLE where they are poised for plasma cell differentiation. Anifrolumab, approved for SLE, targets IFNAR1. We hypothesized that type I and III IFN response and anifrolumab binding are determined by B cell phenotype. Methods Flow cytometry used to immunophenotype SLE and healthy blood and bone marrow (BM). Labeled anifrolumab binding to B cells measured by median fluorescent intensity (MFI). Change in pSTAT1 after IFN-α2 or IFN-λ1 stimulation calculated by phosphoflow. Phenotyping done after in vivo anifrolumab. Results ABC had higher baseline pSTAT1 compared to CD11c- DN1 from the same donor. High IFN donor DN1 had reduced responsiveness to IFN-α but their ABC had greater pSTAT1 after IFN-λ. For all B cell subsets, blood B cells had greater Δ in pSTAT1 after IFN-α2 than their BM-derived counterparts. Circulating naïve cells had highest MFI for anifrolumab compared to double negative, switched memory or unswitched memory B cells. Blood B cells had higher anifrolumab MFI than BM-derived cells. Conclusions Type I and III IFN have differential effects on B cell subsets. Anifrolumab had greater binding to naïve B cells suggesting IFNAR1 expression is downregulated in antigen-experienced cells. Anifrolumab may have greater efficacy against circulating B cells. Funding Sources University of Rochester School of Medicine and Dentistry, Translational Immunology and Infectious Disease Institute Pilot Award (STUDY7028) and NIH/NIAID K08 AI168450-01A1. Topic Categories Basic Autoimmunity (BA)